title: Stereoselective glucuronidation of propranolol in human and cynomolgus monkey liver microsomes: role of human hepatic UDP-glucuronosyltransferase isoforms, UGT1A9, UGT2B4 and UGT2B7.
abstract: The stereoselective glucuronidation of propranolol (PL) in human and cynomolgus monkey liver microsomes, and the roles of human hepatic UDP-glucuronosyltransferase (UGT) isoforms involved in the enantiomeric glucuronidation of PL using recombinant UGT enzymes were investigated. In Michaelis-Menten plots, R- and S-PL glucuronidation by human liver microsomes showed sigmoidal kinetics whereas the kinetics of enantiomeric PL glucuronidation by cynomolgus monkey liver microsomes was monophasic. The Km, Vmax and CLint values of cynomolgus monkey liver microsomes were generally higher than the S50, Vmax and CLmax values of human liver microsomes in R- and S-PL glucuronidation. The glucuronidation of R- and S-PL was catalyzed by at least 3 UGT isoforms: UGT1A9, UGT2B4 and UGT2B7. Michaelis-Menten plots for R- and S-PL glucuronidation by UGT1A9 were monophasic, whereas the kinetics of UGT2B7 showed sigmoidal curves. Enantiomeric R-PL glucuronidation by UGT2B4 showed sigmoidal kinetics, whereas S-PL glucuronidation displayed monophasic kinetics. UGT1A9 showed remarkable stereoselectivity in Vmax and CLint values of R-PL < S-PL. These findings demonstrate that the profiles of enantiomeric PL glucuronidation in human and cynomolgus monkey liver microsomes are largely different and suggest that the human hepatic UGT isoforms UGT1A9, UGT2B4 and UGT2B7 play distinctive roles in enantiomeric PL glucuronidation.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
authors.forename: Keiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizudani
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Akiko
authors.initials: A
authors.lastname: Koeda
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Naito
authors.forename: Shizuo
authors.initials: S
authors.lastname: Narimatsu
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D011433:Propranolol / Q000378:metabolism*; D013045:Species Specificity; D013237:Stereoisomerism; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D020719:Glucuronides; D007527:Isoenzymes; C000715591:UGT1A9 protein, human; D011433:Propranolol; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C486404:UGT2B4 protein, human